The purpose of this K01 application is to support the candidate's advanced training in the field of substance abuse research, and to promote the development of other necessary skills that are characteristic of successful, independent investigators. The candidate's long-term goal is to obtain a tenure-track academic appointment, which would allow him to independently pursue a greater understanding of amphetamine neurotoxicity. To meet these goals, a career development plan has been prepared by the candidate and his mentor, Dr. Donald M. Kuhn, which includes coursework, attendance at seminars and scientific meetings, interactions with consultants, the acquisition of new research techniques and the continued development of manuscript and grant writing skills. Dr. Kuhn's guidance will be supplemented with a small group of consultants who offer the candidate a unique opportunity to acquire additional skills that will further prepare him for scientific independence. The candidate's immediate goals are to elucidate the molecular mechanisms of methamphetamine (METH)-induced neurotoxicity. METH is a powerful stimulant drug of abuse that has become a scourge on American society. In fact, the use of amphetamines, including METH, now exceeds that of cocaine and heroin on a global scale. METH causes persistent reductions of function in dopamine (DA) nerve endings of animals and humans. These neurotoxic effects have been intensely studied for more than twenty years, yet much remains to be learned about how METH damages DA nerve terminals. Recent evidence from our lab and others suggests that microglia, the resident macrophages of the CNS, may contribute to neurotoxicity following a METH exposure. This proposal seeks to elucidate the molecular mechanisms of METH-induced neurotoxicity, with special emphasis on the METHmicroglial relationship, through the use of in vitro (using primary microglia cultures) and in vivo (mouse) models. The working hypothesis of this proposal is that microglia contribute to the neurotoxicity evident in striatum following METH treatment. The specific aims of this proposal are: 1) determine if pre-activation of microglia potentiates a subsequent neurotoxic METH insult;2) determine the extent of METH-induced neurotoxicity in tissue plasminogen activator (tPa) knockout mice which exhibit defective microglial activation;and 3) elucidate the link between substance P (SP) and the activation of microglia following a neurotoxic METH regimen, as mice lacking the SP receptor (NK-1R) do not exhibit METH-induced neurotoxicity. This research is extremely relevant to public health. The use of METH is pervading our society, both nationally and globally, while a growing body of literature demonstrates that METH may lead to long term CNS damage. Therefore, it is imperative to understand the mechanisms of how METH functions, and how it damages the CNS.